We propose to undertake a multi-pronged human genetic analysis on the Afrikaners, a European origin founder population from South Africa, to identify genetic risk factors for both familial and non-familial (sporadic) forms of schizophrenia. Our work during the previous cycle of funding for this grant has provided three important insights in the genetic and biological basis of sporadic and familial forms of the disease: First, that at least 10 percent of sporadic cases of schizophrenia in the Afrikaner population can be accounted for by rare de novo CNVs; second, that a substantial portion of familial cases of schizophrenia can be accounted for by rare inherited CNVs enriched in deletions and duplications of genic regions; and third that a portion of Afrikaner families with schizophrenia carry one or more disease risk genes located at chromosome 13q34. Our work during the last funding period of this award represents one of the first family-based studies to explore the important question of how CNVs contribute to the known inheritance patterns of schizophrenia and dictates the research direction of this project for the next funding cycle. Specifically we plan to (i) undertake a new, high- density genome-wide scan for CNVs using large cohorts of familial and sporadic schizophrenia, as well as control cohorts; (ii) pursue sequencing based approaches to determine whether the total number of potentially damaging mutations or the number of de novo mutations in genes affected by rare CNVs is significantly higher in the cases versus controls; (iii) undertake a comprehensive effort based on two complementary approaches to probe the genetic architecture of the 13q34 schizophrenia susceptibility locus with a final goal to identify one or more common or rare variants accounting for the linkage signal observed in this region. The advantage of doing this research in the unique Afrikaner population cannot be overemphasized. In addition to being an ethnically homogeneous population derived from a small number of founders, the family structure, the potential for genealogical research and the availability of detailed psychiatric records over several generations facilitates family-based studies of schizophrenia and high-confidence distinction of sporadic and familial cases. This project holds tremendous promise to shed light into the genetic etiologies of schizophrenia, especially in the context of newly established technologies that allow efficient screens of rare mutations. PUBLIC HEALTH RELEVANCE: Our recent work has provided important insights into the genetic and biological basis of both familial and non- familial forms of schizophrenia, providing evidence that rare genomic copy number variants (CNVs) play an important role in the genetic risk of both forms of the disease. We propose to pursue further work to characterize the full spectrum of CNVs in schizophrenia and inform the genetic architecture of the disease more fully. We also propose to move beyond the CNV data and characterize in a comprehensive manner (using next generation sequencing approaches) genes located in identified disease risk loci, for additional RARE mutations that affect the function or expression of these genes.